The central hypothesis of this program project application is that the pathogenesis of HIV encephalopathy may involve either direct mechanisms in which highly restricted HIV infections of glia or neurons lead to neuronal dysfunction, or indirect mechanisms in which infected microglial cells, produce viral proteins, cytokines or chemokines which in turn act on glia or neurons leading to dysfunction. The Neuropathology Core will continue to explore these hypotheses by studies of the brains of patients dying with HIV infection. These brains will be used for two purposes, (i) as a tissue bank to support studies under other projects in this program, and (ii) histologically based studies to compare the cellular distribution of HIV, cytokines, chemokine and their receptors and growth factors (e.g. PDGF), to pathological lesions and proliferation markers of astrocytes (GFAP) microglia and endothelial cells (RCA-1). (I) Tissue bank. About 5-10 brains will be collected each year under the aegis of the autopsy service at the Hospital of the University of Pennsylvania. These brains, in addition to the existing collection of 25 brains will constitute a tissue bank, with tissues stored in various ways to optimize them as a resource for other projects under this program, including PCR amplification of gene sequences, and histological section based studies of viral chemokine receptors mRNA, and standard neuropathological stains. (ii) Neuropathological mapping. Selected brains will be used to map the distribution of neuropathological lesions, distribution of HIV genome by in situ PCR, HIV antigen by immunohistochemistry, and mRNA by in situ hybridization for selected chemokines, chemokine receptors, growth factors (PDGF), and markers of cell proliferation such as GFAP and RCA-1. (iii) Assistance with the design and interpretation of morphological and neuropathological studies of other projects including the analysis of cell cultures and mouse brains.
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